Hydrocortisone Acetate Suppository Formulation For Treatment Of Disease

ABSTRACT

The present invention relates, in various embodiments, to formulations comprising hydrocortisone and silicon dioxide. In additional embodiments, the invention relates to suppositories comprising hydrocortisone and silicon dioxide. The formulations of the present invention are useful for administration to patients who have gastrointestinal diseases and disorders such as, for example, inflammatory bowel disease.

RELATED APPLICATIONS

This application is a Divisional Application of U.S. application Ser.No. 15/555,325, filed Mar. 10, 2016, which is the U.S. National Stage ofInternational Application No. PCT/US2016/021842, filed Mar. 10, 2016,which designates the U.S., published in English, and claims the benefitof U.S. Provisional Application No. 62/131,944, filed Mar. 12, 2015. Theentire teachings of the above applications are incorporated herein byreference.

BACKGROUND OF THE INVENTION

Hydrocortisone delivered rectally has been established as a strongtherapeutic treatment for certain medical conditions, includingleft-sided, distal ulcerative colitis. Advantages of rectallyadministered hydrocortisone (e.g., hydrocortisone acetate) includeextremely low levels of systemic absorption and fewer side effects thanare often experienced with oral and intravenous corticosteroidtreatments. Current rectal drug formulations of hydrocortisone includeliquid enemas, foam enemas and semi-solid suppositories. Currentprescribing habits for rectal drug formulations of hydrocortisoneinclude an assessment of the severity of the disease as well as theextent of disease activity within the colon.

Rectally-delivered hydrocortisone has been shown to induce remission inpatients with left-sided, distal ulcerative colitis. For patients withthis disease, liquid enemas are often prescribed because the medicationis distributed as far as the splenic flexure. For patients with sigmoidcolitis, foam enemas are prescribed as the distribution of themedication extends to the sigmoid colon and partially to the descendingcolon. Although ulcerative colitis confined to the rectum, defined asulcerative proctitis, can be treated with suppository formulations ofhydrocortisone, no suppository formulation of hydrocortisone has beenapproved by the Food and Drug Administration (FDA) as a safe andeffective treatment.

Accordingly, there is a need for safer and more effective hydrocortisonesuppository formulations for the treatment of gastrointestinal (GI)diseases and disorders, including ulcerative colitis, Crohn's diseaseand inflammatory bowel disease (IBD).

SUMMARY OF THE INVENTION

The present invention is based, in part, on the discovery offormulations of hydrocortisone having certain desirable properties andcharacteristics that render these formulations suitable foradministration as a suppository to treat ulcerative colitis and othergastrointestinal diseases that are treatable with hydrocortisone.

Accordingly, in one embodiment, the present invention relates to aformulation comprising about 0.01% to about 25% by weight hydrocortisoneacetate and about 0.001% to about 5% by weight colloidal silicondioxide. In a particular embodiment, the formulation comprises about0.5% to about 5% by weight hydrocortisone acetate and about 0.1% toabout 5% by weight colloidal silicon dioxide. In a further embodiment,the formulation comprises about 4.5% by weight hydrocortisone acetateand about 0.7% by weight colloidal silicon dioxide. In some embodiments,the formulation additionally comprises an oleaginous base that includestriglycerides. In additional embodiments, the formulation also comprisesbutylated hydroxytoluene (BHT).

In other embodiments, the present invention relates to a suppositoryhaving a weight of about 2 grams (g), which comprises about 90milligrams (mg) hydrocortisone acetate, and releases at least about 80%of the hydrocortisone acetate at about 180 minutes following exposure todissolution media comprising a buffered 5% w/v sodium lauryl sulfatesolution having a final pH in the range of about 6.8-7.0. In aparticular embodiment, the suppository comprises about 90 mghydrocortisone acetate, colloidal silicon dioxide, and an oleaginousbase that includes triglycerides. In a particular embodiment, thesuppository weighs about 2 g.

The formulations described herein have advantages over priorhydrocortisone suppository formulations, including, for example,improved retention by patients and reduced absorption variability. Thedisclosed formulations also have desirable release profiles ofhydrocortisone acetate upon exposure to rectal fluid and, therefore, areless dependent than current hydrocortisone suppository formulations onmelting temperature for the delivery of hydrocortisone to the patient.

In addition to the foregoing, embodiments of the invention are directedto the structure of the suppository. As known, certain diseases aretreated by way of a suppository containing a drug (e.g., hydrocortisoneacetate). Current suppositories have “torpedo” configurations and,therefore, can be difficult to apply in a rectum to effectuate a highlevel of drug delivery. Embodiments of the present invention provide foralternative configurations of suppositories that allow for easierapplication into the rectum and can provide greater surface area of themedication for which to expose tissues within the rectum.

Another embodiment of the invention is a drug delivery system (e.g., asuppository) that includes a component that changes shape or compositiononce inside the body and releases medication (e.g., hydrocortisoneacetate) after being placed within the rectum. The component can becompact in shape and size for the administration into the body. Once thecomponent is properly placed within the rectum, or at the anal-rectalline, the component changes shape or composition to administer themedication contained therein. The drug delivery component may be made ofsynthetic or biodegradable polymer impregnated with a medication.Alternatively, the component may be made of a metal with a polymercoating that is impregnated with the medication. The component may becomposed of a water soluble base in combination with the drug.Alternatively, the component may encase or coat the drug in a watersoluble film or coating.

One example embodiment includes a flexible ring that is made compact inshape and size before administration to the patient. The ring may betwisted or coiled to form a smaller ring within a ring. Alternatively,the ring may be folded to form a narrow loop, and, additionally, theends of the narrow loop may be folded in on itself in the oppositedirection, forming a compact shape of the ring. The ring may also beself-elongating in that it holds a small circumference before beingplaced within the body, at which time it expands in circumference to fitwithin the rectum.

Another embodiment includes a “tree” shape drug delivery componentconfigured to fold into a compact formation until the proper placementwithin the body. The component may have one or more sections at the topof the tree that may fold down to a form “I” formation beforeadministration. The component may or may not have a center stem.Alternatively, the sections at the top of the tree may beself-elongating in that they hold the “I” formation beforeadministration and extend to the tree formation after proper placementwithin the body.

The embodiments of the ring or tree shapes may have medicated filamentsthat attach to the component. The medicated filaments may hang from thecomponent within the body to treat a larger area of the mucosa lining ofthe rectum. The filaments may degrade within the body or be expelledfrom the body after releasing the medication.

An alternative drug delivery system includes a fabric impregnated withmedication or a film composed of the medication. The fabric may befolded or wound on itself before administration. After proper placement,the fabric may be unfolded or unwound to adhere to the lining of therectum.

Another example embodiment includes a sponge impregnated with medicationthat is folded, compressed or wound on itself before administration tohold a more compact shape. After administration, the sponge may expand,unfold, or unwind to fit the shape and location within the rectum.

Another drug component includes a container that holds the medication ina compact shape or form until it is properly placed within the body. Oneexample embodiment includes a water-soluble shell surrounding a drugcomposition. Once the drug component is properly placed within therectum, the outer shell dissolves. The medication within the shellexpands or changes shape or form and releases the drug to be absorbed bythe body. The medication, in a solid state, may be formed in a varietyof structural shapes as disclosed herein. When packaged within adelivery vessel, such as an inactive ingredient that is designed tochange state over time after placement within the body to releasemedication contained therein, the medication may include, but is notlimited to, the following forms: powder, liquid, gel, granule, orthreads. The medication may increase its contact with the mucosa liningof the rectum by expanding in volume. Alternatively, the medication mayincrease its contact with the mucosa lining of the rectum by greaterdisbursement of the drug after being freed from the constraints of theouter shell.

Another embodiment includes a water soluble shell surrounding a solid orsemi-solid drug that expands or takes a different shape after the drugcomponent is properly placed within the body.

The drug components described in this application can be administered tothe patient using an insertion applicator to achieve proper placementwithin the body.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing a dissolution profile for eight prototypehydrocortisone formulations in media that mimics rectal fluid.

FIG. 2 is a graph showing the hydrocortisone acetate release profile ofseven prototype hydrocortisone formulations.

FIG. 3 is a diagram of a medicated drug component according to anembodiment of the present invention within a device configured to insertthe component into a rectum.

FIGS. 4A and 4B are diagrams of ring or other shaped embodiments ofmedicated drug components.

FIGS. 5A-5C are diagrams illustrating a sequence by which a suppositoryinsertion device according to an embodiment of the present invention isused to insert a suppository (e.g., a medicated drug component) into arectum.

FIGS. 6A and 6B are diagrams of tree-shaped embodiments of the medicateddrug component.

FIG. 6C is another embodiment of the drug component.

FIGS. 7-9 are diagrams of other embodiments of the medicated drugcomponent.

FIGS. 10A and 10B are flow diagrams indicating example applicationtechniques for the mediated drug component.

DETAILED DESCRIPTION OF THE INVENTION

A description of example embodiments of the invention follows.

In one embodiment, the invention relates to a formulation comprisinghydrocortisone (e.g., hydrocortisone acetate) and silicon dioxide (e.g.,colloidal silicon dioxide). In some embodiments, the formulationcomprises about 0.01% to about 25% by weight hydrocortisone acetate. Forexample, the formulation can comprise about 0.02% to about 1.0%, about0.03% to about 0.1%, about 0.4% to about 10.0%, about 3.0% to about8.0%, about 4.0% to about 7.0%, or about 4.0% to about 5.0% by weighthydrocortisone acetate. In another embodiment, the formulation comprisesabout 0.5% to about 5% by weight hydrocortisone acetate. In a particularembodiment, the formulation comprises about 4.5% (e.g., 4.0%, 4.5%,5.0%) by weight hydrocortisone acetate.

In some embodiments, the formulation comprises about 0.001% to about 5%by weight colloidal silicon dioxide. For example, the formulation cancomprise about 0.002% to about 1%, about 0.003% to about 0.1%, about0.004% to about 0.05%, about 0.4% to about 1.5%, or about 0.5% to about1.0% by weight colloidal silicon dioxide. In another embodiment, theformulation comprises about 0.1% to about 5% by weight colloidal silicondioxide. In a particular embodiment, the formulation comprises about0.7% (e.g., 0.6%, 0.7%, 0.8%) by weight colloidal silicon dioxide.

In additional embodiments, the formulation further comprises apharmaceutically-acceptable excipient (e.g., apharmaceutically-acceptable excipient other than colloidal silicondioxide). In some embodiments, the formulation comprises apharmaceutically-acceptable excipient that is an oleaginous base. Theoleaginous base can be naturally occurring, semi-synthetic or synthetic.In certain embodiments, the oleaginous base includes glycerides (e.g.,monoglycerides, diglycerides and triglycerides). For example, theoleaginous base can include a mixture of monoglycerides, diglyceridesand triglycerides, in a variety of ratios. In a particular embodiment,the oleaginous base includes triglycerides (e.g., more than 50% of theglyceride content is triglycerides).

Suitable oleaginous bases for use in the formulations described hereininclude, for example, theobroma oil/cocoa butter, triglycerides fromvegetable oils, hydrogenated coco-glycerides, trilaurin triglycerides(glycerol trilaurate, glyceryl trilaurate, glyceryl tridodecanoate,glycerin trilaurate and tridodecanoin), lecithin and hydrogenatedlecithin, synthetic or semi-synthetic triglycerides and mixturesthereof. In some embodiments, the formulation includes triglyceridesfrom a hydrogenated vegetable oil. The vegetable oil can be, e.g., apalm oil, a palm kernel oil, a cottonseed oil, a soybean oil, a rapeseedoil, a coconut oil, a peanut oil, a sunflower seed oil or an olive oil.In other embodiments, the oleaginous base is a semi-synthetic glyceridebase comprising saturated C8-C18 triglyceride fatty acids and lecithin.In a particular embodiment, the oleaginous base comprises at least about85% triglycerides, and further comprises diglycerides and monoglycerides(e.g., less than about 15% diglycerides and less than about 1%monoglycerides). Examples of commercially available oleaginous basesthat are useful for the formulations described herein include, forexample, WECOBEE® M bases, HYDRO-KOTE® C and 112 bases, WITEPSOL® H-15bases, and SUPPOCIRE® A, AS2, AML, and BS2 bases.

In other embodiments, the formulation comprises apharmaceutically-acceptable excipient that is a water-soluble misciblebase. Examples of water-soluble miscible bases include glycerinatedgelatins or polyethylene glycol (PEG) polymers (e.g., PEG 300, PEG 1450,PEG 3350, PEG 6000, PEG 8000).

In certain embodiments, the formulation further comprises an additive(e.g., one additive, two or more additives). Additives include, but arenot limited to, adsorbents, surface acting agents (e.g., mucosaladhesives, such as xanthan gum, lisinopril, hydroxypropylmethylcellulose, carboxy methylcellulose, and chitosan, among others),viscosity-influencing agents, suspending/dispersing agents (e.g., zincoxide, alginic acid, crystalline cellulose), plasticizers (e.g.,diethlyhexyl phthatale, glycerin), melting point-adjusting agents (e.g.,white wax), antimicrobial agents (e.g., thimerasol), phospholipides(e.g., lecithin) and antioxidants (e.g., ascorbic acid, ascorbicpalmitate, butylated hydroxytoluene (BHT), butylated hydroxyanisole(BHA)).

In some embodiments, the formulation comprises an additive that is anantioxidant. Particular examples of antioxidants that are suitable forinclusion in the formulations described herein include butylatedhydroxytoluene (BHT) and butylated hydroxyanisole (BHA), as well ascombinations BHT and BHA, in a variety of ratios (e.g., a 1:1 ratio). Ina particular embodiment, the formulation comprises butylatedhydroxytoluene (BHT). For example, the formulation can comprise about0.001% to about 0.1%, about 0.005% to about 0.03%, or about 0.0095% toabout 0.015% by weight BHT. In a particular embodiment, formulationcomprises about 0.01% (e.g., 0.0095%, 0.010%, 0.015%) by weight BHT.

In general, the formulations described herein are solid or semi-solidformulations. Accordingly, in various embodiments, the formulations ofthe present invention are suitable for use in a suppository foradministration (e.g., rectal administration) to a mammal (e.g., ahuman). Typically, the formulations described herein have one or moreproperties (e.g., melting temperature, solubility, stability) that aredesirable for suppositories. For example, in some embodiments, theformulation releases the hydrocortisone acetate upon exposure to rectalfluid. Methods for assessing whether a formulation releases thehydrocortisone acetate upon exposure to rectal fluid are known in theart and include, for example, the method exemplified herein.

In additional embodiments, the formulation has a melting temperature inthe range of about 35° C. to about 41° C., preferably about 36° C. toabout 40° C., more preferably about 37° C. to about 39° C. Methods fordetermining the melting temperature of a formulation are known in theart and include, for example, the method exemplified herein.

In some embodiments, the formulation is stable (e.g., under storageconditions) at a temperature in the range of about 25° C. to about 40°C. Methods for assessing whether a formulation is stable under storageconditions are known in the art and include, for example, the methodexemplified herein.

In other embodiments, the invention relates to a suppository having aweight of about 2 grams (g), which comprises about 90 milligrams (mg)hydrocortisone acetate, and releases at least about 80% of thehydrocortisone acetate at about 180 minutes following exposure todissolution media comprising a buffered 5% w/v sodium lauryl sulfatesolution having a final pH in the range of about 6.8-7.0. In aparticular embodiment, the dissolution media comprises 5% w/v sodiumlauryl sulfate:acetate buffer pH 5.0 (70:30) final pH adjusted to6.8-7.0.

Suitable concentrations of hydrocortisone acetate for use in thesuppositories described herein include, for example, any of theconcentrations of hydrocortisone acetate described herein as beingsuitable for the formulations of the invention. Suitable concentrationsof colloidal silicon dioxide for use in the suppositories describedherein include, for example, any of the concentrations of colloidalsilicon dioxide described herein as being suitable for the formulationsof the invention. In one embodiment, the suppository comprises 90 mg ofhydrocortisone (e.g., hydrocortisone acetate) and about 5 mg to about 20mg (e.g., about 14 mg) of colloidal silicon dioxide.

In some embodiments, the suppository further comprises an oleaginousbase. In one embodiment, the oleaginous base includes triglycerides.Suitable oleaginous bases for use in the suppositories described hereininclude, for example, a semi-synthetic glyceride base comprisingsaturated C8-C18 triglyceride fatty acids and lecithin, or comprising atleast about 85% triglycerides, wherein the base further comprisesdiglycerides and monoglycerides.

In additional embodiments, the suppository further comprises anadditive. Suitable additives for use in the suppositories describedherein include, for example, any of the additives described hereinaboveas being suitable for the formulations of the invention. In a particularembodiment, the suppository comprises BHT. Suitable concentrations ofBHT for use in the suppositories described herein include, for example,any of the concentrations of BHT described hereinabove as being suitablefor the formulations of the invention.

The suppositories described herein can have a weight in the range ofabout 500 mg to about 5 g and generally include from about 5 mg to about200 mg of hydrocortisone (e.g., hydrocortisone acetate). In a particularembodiment, the suppository weighs about 2 g (e.g., 1.8 g, 1.9 g, 2.0 g,2.1 g, 2.2 g). In one embodiment, the suppository weighs about 2 g andcomprises about 90 mg (e.g., 85 mg, 90 mg, 95 mg) hydrocortisoneacetate. In a further embodiment, the suppository weighs about 2 g andcomprises about 90 mg hydrocortisone acetate and about 14 mg (e.g., 12mg, 13 mg, 14 mg, 15 mg, 16 mg) colloidal silicon dioxide. In a furtherembodiment, a suppository weighs about 2 g and comprises about 90 mghydrocortisone acetate, about 14 mg colloidal silicon dioxide and about0.2 mg (e.g., 0.15 mg, 0.20 mg, 0.25 mg) BHT.

In some embodiments, the suppository has a weight of about 2 g,comprises about 90 mg of hydrocortisone acetate, and releases at leastabout 80% of the hydrocortisone acetate at about 180 minutes followingexposure to a dissolution media comprising 5% w/v sodium laurylsulfate:acetate buffer pH 5.0 (70:30) final pH adjusted to 6.8-7.0.

In some embodiments, the present invention relates to a suppositoryhaving an oblong shape. In other embodiments, the oblong shape furthercomprises a cylindrical shape. In certain embodiments, the suppositoryhas a shape that allows contact between the outer surface of thesuppository and the mucosal membrane of the rectum when the suppositoryis situated in the rectum. In other embodiments, the suppositoryformulation releases the hydrocortisone acetate upon exposure to rectalfluid.

Methods and devices for administering suppositories are known in the artand include, for example, those described in U.S. Pat. No. 8,192,393 B2,the contents of which are incorporated herein by reference in theirentirety. Such methods and devices are useful for administration of theformulations (e.g., suppositories) described herein.

The formulations (e.g., suppositories) described herein are useful forthe treatment of gastrointestinal diseases and disorders, including, forexample, inflammatory bowel disease (IBD), bowel ailments and otherdiseases for which systemic or local rectal hydrocortisone is anappropriate therapeutic intervention. Such gastrointestinal diseases anddisorders include, but are not limited to, colitis (e.g., ulcerativecolitis, collagenous colitis, lymphocytic colitis), Crohn's disease,proctitis (e.g., ulcerative proctitis), and hemorrhoids (e.g., internalhemorrhoids).

In some embodiments, the formulations (e.g., suppositories) describedherein can be administered in combination with other therapeutic agentsthat are useful for treating gastrointestinal diseases and disorders. Inone embodiment, the formulations (e.g., suppositories) described hereincan be administered in combination with mesalamine (e.g., oralmesalamine, a suppository containing mesalamine). In general, the otheragent(s) being administered in combination with the hydrocortisoneformulations will be administered separately from the hydrocortisoneformulation (e.g., in a different form (e.g., a pill or capsule) orsuppository). In some embodiments, the formulations (e.g.,suppositories) described herein can be administered in combination witha local anesthetic (e.g., lidocaine).

Ailments and diseases of the bowel are common and have varying degreesof severity. One of the difficulties of treating patients with boweldisorders and symptoms is targeting the affected area. Oral medicationsmust pass through the metabolism before offering therapeutic benefit andare systemic in their reach. Increasingly, the intravenous infusiontherapies are being used to treat bowel disease and are targeted tomodify the immune system.

One subset of patients with digestive disease suffer from ulcerativeproctitis which affects the rectum and cannot be treated with oral orintravenous medications. Treatment for ulcerative proctitis is bestaccomplished with local therapy using medications that can treat thevenous inflammation topically. Current drug therapy for ulcerativeproctitis includes the use of suspension enemas, suppositories andcreams or ointments. In the case of internal ulcers, the target area isthe anal-rectal line and the lower rectum where inflamed veins originateand are sometimes prolapsed.

Suspension enemas are designed to treat the sigmoid or left side of thecolon and place the drug too far above the lower rectum and the affectedarea. Enema medication is also difficult to retain, and often patientsmust be sedated in order to complete the therapy. Suppositoriesadministered with a finger are placed too shallow within the anal canaland do not reach the lower rectum and anal-rectal line. Additionally,the suppository medication is difficult to retain and often leaks frominside to outside the body. Creams and ointments are primarily used totreat external sores and, when used internally, do not reach thetargeted area for ulcers due to ulcerative proctitis inside the rectumat or above the anal-rectal line.

A drug component that places medication in the targeted location of thelower rectum is the optimal way to treat ulcerative proctitis. Whenplaced in the targeted location, not only does the drug avoid contactwith the sphincter muscles that signal the brain to release the contentsof the colon, but also the drug is placed at the origins of hemorrhoidinflammation.

Targeted topical therapy would be a benefit in the treatment ofinflammatory bowel disease, in particular, ulcerative proctitis.Affecting the lower six inches of the colon, ulcerative proctitis isbest treated with topical therapy. However, in order to prevent theadvancement of the disease, the area of treatment should be at thehighest point of the inflammation. Treatment of ulcerative proctitispatients has similar drawbacks to the treatment of resulting ulcers withsuspension enemas and suppositories.

FIG. 3 illustrates the use of an insertion applicator 300 for theadministration of a drug component into the body of the patient in itspre-insertion shape or form. An example of an insertion applicator isdescribed in U.S. application Ser. No. 12/287,215, entitled “Method AndApparatus For Inserting A Rectal Suppository,” filed on Oct. 7, 2008,now U.S. Pat. No. 8,192,393, the entire teachings of which areincorporated herein by reference. In an example embodiment, the drugcomponent 302 is placed in a distal end 308 of an insertion barrel 304in its pre-insertion form or shape. In a different example embodiment,the drug component 302 is placed in a proximal end 310 of the barrel304. A plunger 306 is thereafter placed in the proximal end of thebarrel 304. After inserting the applicator 300, filled with the drugcomponent, into the anus, the plunger 306 is advanced from the proximalend to the distal end of the barrel, thereby releasing the drugcomponent 302 to the proper positioning within the rectum (see alsoFIGS. 5A-5B). Once the drug component 302 is properly positioned withinthe body, the drug component changes shape or form and releases itstherapeutic medication to the mucosa lining of the rectum (see also FIG.5C).

FIG. 4A illustrates example embodiments of folded (collapsed) medicatedrings 402 a, 402 b, 402 c, and 402 d′ (collectively 402) in theirpre-insertion shape and their new shape after proper positioning withinthe body. After deployment, the medicated ring 402 unfolds, uncoils, orexpands (412 a, 412 b, 412 c, 412 d) depending on the way it wascompressed to the smaller shape. The medicated ring 402 unfolds orexpands to a size whereby it is thereafter configured to press on tissueof the rectum (see also FIG. 5C). The unfolded or expanded state of ring402 is indicated for the example embodiments in FIG. 4A at 402 a′, 402b′, 402 c′ and 402 d″. Once in position, the medicated ring 402 releasesthe medication contained within the component. The component thereaftereither degrades within the body or is released during the evacuation ofthe contents of the colon.

As illustrated in FIG. 4A, a flexible ring 402 is made compact in shapeand size before administration to the patient. For example, ring 402 amay be twisted or coiled to form a smaller ring (loop) within a ring(loop). The ring 402 a untwists or uncoils (412 a) after properplacement within the body. In another example, ring 402 b may be foldedto a loop in a long “I” formation before placement and is configured tounfold (412 b) after placement within the body. A ring 402 c may also beself-elongating (e.g., self-expanding, as shown at 412 c) in that itholds a small circumference before and until being placed within thebody, at which time it expands in circumference to fit within therectum. Alternatively, ring 402 d-1 may be folded to form a narrow loop402 d-2, and, additionally, opposite ends of the narrow loop may befolded in on themselves (402 d-3), forming a compact shape of the ring402 d′ before insertion. The ring 402 d′ then unfolds (412 d) to anexpanded shape 402 d″, after proper placement.

FIG. 4B illustrates cross sections of drug components, such as rings 402of FIG. 4A, that may be circular 414 in cross section or straight (e.g.,flat) 416 in cross section. An outer side of the drug components mayhave one or more raised bumps to aid in the adherence to the mucosalining of the rectum. For example, component 418 is circular in crosssection and includes raised bumps 417 arranged around its perimeter. Inanother example, component 420 is flat in cross section and includesraised bumps 419 on at least one side. Alternatively, the drugcomponents may be corrugated 422 with alternating grooves 421 that aidin the positioning within the rectum.

FIGS. 5A-5C illustrate a process by which a person inserts a suppository(e.g., a medicate drug component) 502 into a rectum 524 through use of asuppository insertion device 500 according to an embodiment of thepresent invention. In FIG. 5A, a barrel 504 of the insertion device 500is inserted into an anal canal 526 below the anal-rectal line 528. Asuppository 502 and plunger 506 may be inside the barrel 504 during theinsertion of the barrel. In FIG. 5B, the person pushes the plunger 506toward the anal-rectal line 528, which, in turn, pushes the suppository502 toward and into the rectum 524, at or above the anal-rectal line andpast the sphincter muscles 530. Once released from the insertion device500, the suppository 502 can change shape or form, e.g., expand, asillustrated at 502′. FIG. 5C illustrates the suppository in an expandedform 502″ in which the suppository's expanded size causes it to havecontact with internal walls of the rectum 524. The applicator 500 iswithdrawn, leaving the suppository in place. The suppository 502″ isthereafter removed from the rectum through normal discharge of contentsfrom the bowel in accordance with various embodiments of thesuppository, as described herein.

FIGS. 6A and 6C illustrate example embodiments of folded medicated treecomponents 602 a, 602 b, 602 c, 602 d, and 602 e (collectively, 602) intheir pre-insertion shape and their new shape 602 a′, 602 b′, 602 c′,602 d′ and 602 e′ after proper positioning within the body. Themedicated tree 602 unfolds or self expands (612 a, 612 b, 612 c, 612 d,612 e) depending on the way it was compressed to the smaller shape. Themedicated tree 602 unfolds or expands to a size whereby it will beconfigured to press on the tissue of the rectum. The tree 602 may have acenter stem (632 a, 632 b, 632 d, 632 e) or a center ring (see, e.g.,636 h and 636 i in FIG. 6B) from which the arms (634 a, 634 b, 634 d,634 e) of the tree radiate. Alternatively, a tree 602 c can have arms634 c radiating from a central point and not have a center stem. Once inposition, the medicated tree releases the medication contained withinthe drug component. The drug component either degrades within the bodyor is released during the evacuation of the contents of the colon.

The “tree trunk” may be made of the same material as the “branches” ofthe tree and degrade in the body. Alternatively, the tree trunk may bemade of a soft cushiony material that causes no harm and holds a shapethat can be expelled with the contents of the bowel.

FIG. 6B illustrates top views of tree-shaped drug components. Thetree-shaped drug components (602 f, 602 g, 602 h and 602 j) may have oneor more arms (634 f, 634 g, 634 h and 634 j) radiating out from a centerposition (632 f, 632 g, 632 h, 632 j). The arms may be in a straightstick (634 f, 634 j) or a petal formation (634 g, 634 h). The arms maymeet at the center point (632 f, 632 g) or they may radiate from a ring(636 h, 636 j) surrounding the center point (632 h, 632 j), therebyallowing gas to flow through the center of the drug component.

FIG. 6C illustrates a tree drug component 602 e unfolding (612 e) upsidedown, with the center post 632 e and the free ends of the tree branches634 e entering the body first.

FIG. 7 illustrates medicated filaments (e.g., mediated threads) attachedto the drug component. Three example configurations are shown. One ormore medicated filaments 740 a, 740 b, and 740 c can be attached, orotherwise coupled, to a ring-shaped drug component 702 a, tree-shapeddrug component 702 b (having a center portion and arms), andflower-shaped drug component 702 c (having a center stem and petals). Adrug (e.g., an active ingredient) can be carried by or embedded into thefilaments. The medicated filaments 740 a, 740 b, 740 c may hang from thecomponent within the body to treat a larger area of the mucosa lining ofthe rectum. The filaments may degrade within the body or be expelledfrom the body after releasing the medication.

FIG. 8 illustrates a medicated film 802 a and a medicated fabric 802 b.The drug and a water soluble binding agent may compose the film 802 a.The fabric 802 b may be impregnated with the drug or have raised bumpson the fabric that contain the drug. Both embodiments can be rolled (802c), folded (802 d′) or draped (802 e) before insertion, and can unwind(812 c) or unfold (812 d, 812 e) to a new shape (802 c′, 802 d″ and 802e′) after proper placement within the body. The film or fabric may befolded multiple times, e.g., along one axis (802 d-1) and then alonganother, e.g., perpendicular, axis 802 d-2. The fabric or film mayadhere to the lining of the rectum and deliver the medication to thearea within which it comes in contact. The medicated film or fabricprovides localized therapy to an affected area, which can be of benefitwhen treating specific areas of the colon, for example, the anal-rectalline, where the swelling of hemorrhoid veins originate.

FIG. 9 illustrates medicated sponges 902 a, 902 b, 902 c and 902 d(collectively, 902) that can be compressed (902 a), wound on itself (902b), or folded (902 c, 902 d) to take a smaller pre-insertion shape andsize. Folding can include folding the sponge once (902 c-1), asillustrated, or multiple times, e.g., along different axes. After properpositioning within the body, the sponges 902 may expand (912 a), unwind(912 b), or unfold (912 c, 912 d) to a new shape (902 a′, 902 b′, 902 c′and 902 d′) and release the medication within.

FIG. 10A illustrates various embodiments of water soluble shells 1042 a,1042 b, 1042 c, and 1042 d (collectively, 1042) that contain medication.The shells can have any suitable shape, such as spherical, cylindrical,rectangular and triangular and the like. The medication includes anactive drug ingredient and can be contained in the shell in a stableform. The shells 1042 are configured to dissolve (1044) and release(1046) the medication. The medication, which may be contained in theshell 1042 in any suitable form, can be released in a new form 1048,such as powder or granules 1048 a, embedded or attached to filaments1048 b, a liquid 1048 c, or a gel 1048 d. The new form can differ fromthe stable form.

FIG. 10B is a flow diagram 1050 illustrating an example of the change ina form that the drug component makes after proper positioning in thebody. The drug component may be administered to the patient using aninsertion applicator. At 1052, a drug component is provided thatincludes medication contained in a shell or other suitable container. At1054, the drug component is administered to achieve proper positioningin the body. Once properly positioned in the body, the shell dissolves(1056), thereby allowing the medication to be released in a new form(1058), including, but not limited to, powder or granules, filaments,liquid or gel (see also FIG. 10A). At 1060, the medication may becompletely absorbed by the body. Alternatively or in addition, inactiveingredients in the formulation may be expelled with the contents of thecolon. There may be more than one change in form. After a firstdissolution of an outer shell and release of a medication, there may bea second shell to dissolve and, thus, release another treatment ofmedication in the same or different form from the first release.

As used herein, the term “about” when used in the context of the weightof a suppository, or the amount or percent by weight of a particularingredient in a formulation, means the absolute stated value and othervalues proximal to the stated value that are sufficient to achieve aformulation that has an appropriate melting temperature, stability anddissolvability for use as a suppository. Appropriate meltingtemperatures, stability and dissolvability for a suppository, andmethods for determining such properties of a formulation (e.g.,suppository), are disclosed herein.

In contrast, the term “about” when used in the context of a temperature,means the absolute stated value and other values within a range of +/−2%of the stated value.

EXEMPLIFICATION Example 1: Composition of Hydrocortisone SuppositoryFormulations

Several different prototypes of hydrocortisone formulations were made byformulating 90 mg of hydrocortisone acetate with one or more excipientsinto a 2 g suppository. The excipients tested included the polyethyleneglycol bases PEG 300, PEG 1450, PEG 3350, PEG 6000, and PEG 8000, andthe oleaginous bases WECOBEE® M, HYDRO-KOTE® C and HYDRO-KOTE® 112,WITEPSOL® H-15, and SUPPOCIRE® A, AS2, AML, and BS2. A subset of theseinitial prototypes also included either colloidal silicone dioxide oralginic acid as a suspending/dispersing agent.

Selection criteria were established. The top level criteria were meltpoint, stability and dissolution (release of the drug) (see Example 2herein).

Second level criteria were hardness, consistency, suspension andappearance. Formulations that were too soft or brittle, showed signs offracture or cracking, exhibited clumping or settling, or signs of waterdeveloping between the suppository and the shell were eliminated.

The final criterion was release from the casing. Formulations that weredifficult to remove from the shells after cooling due to sticking wereeliminated.

Upon evaluation, eight formulations, designated prototype numbers 36-43,were selected for further development and testing. The compositions ofthese eight formulations are indicated in Table 1. Each of these eightprototypes included colloidal silicon dioxide as an additive. Colloidalsilicon dioxide is an adsorbent and is widely used in drugs, food, andeven wine. This additive was important for preventing the hydrocortisoneacetate from clumping and settling. In addition, the colloidal silicondioxide facilitated keeping the hydrocortisone acetate in suspension,and promoted desired levels of consistency, dispersal, stability andrelease.

TABLE 1 Composition of Eight Prototype Hydrocortisone FormulationsPrototype # Composition 36 SUPPOCIRE ® A + colloidal silicon dioxide +HCA 37 SUPPOCIRE ® AS2 + colloidal silicon dioxide + HCA 38 SUPPOCIRE ®AML + colloidal silicon dioxide + HCA 39 SUPPOCIRE ® BS2 + colloidalsilicon dioxide + HCA 40 WECOBEE ® M + colloidal silicon dioxide + HCA41 HYDRO-KOTE ® 112 + colloidal silicon dioxide + HCA 42 HYDRO-KOTE ®112 + colloidal silicon dioxide + HCA + BHT 43 HYDRO-KOTE ® 112 + HCA

Example 2: Properties of Hydrocortisone Formulations

The eight prototype formulations selected in Example 1 were tested formelt point, stability and dissolution.

To assess melting point, each suppository containing one of the eightformulations was cut into three slices to produce a small, medium andlarge (large indicating that it fills the entire sample adaptor) slice,each of which was analyzed further to determine the drop point, which isthe moment the first drop falls from the suppository. This was done toensure that the size of the slice did not affect the drop point that wasrecorded. The slices were placed in a heating apparatus containing anoil bath and the temperature was increased steadily over time. At themoment the first drop fell from the suppository, both the temperature ofthe sample and the temperature of the oil bath were recorded. Then, theaverage sample temperature of the three drop points was calculated andused as the melting point for the formulation. Six of the prototypeswere shown to have a melting point in the desired range of 37° C. to 39°C. after six weeks under storage conditions (see Table 2). The storageconditions included maintaining the formulations at a temperature of 25°C./60% relative humidity (RH) or 40° C./75% RH for 2, 4 or 6 weeks. Thetwo formulations outside of the desired temperature range arehighlighted in Table 2.

TABLE 2 Melting point data after 6 weeks in storage. Melting MeltingMelting Melting Melting Prototype temperature temperature temperaturetemperature temperature Average composition (° C.) Trial 1 (° C.) Trial2 (° C.) Trial 3 (° C.) Trial 4 (° C.) Trial 5 (° C.) HCA + CS + Wecobee37.50 39.00 39.00 38.50 40.50 38.90 HCA + CS + Supp. AS2 39.00 38.2538.50 40.50 39.00 39.05 HCA + CS + Supp. A 37.75 37.50 38.50 39.50 38.0038.25 HCA + CS + Witepsol H-15 37.25 36.00 38.00 36.00 39.00 37.25 HCA +CS + Supp. AML 38.25 38.00 38.25 37.00 37.50 37.80 HCA + CS + Supp. BS239.50 38.50 39.00 37.50 39.00 38.70 HCA + CS + Hydrokote 112 43.00 43.5042.00 43.50 42.00 42.80 HCA + CS + BHT + 42.50 42.50 41.00 44.50 NA42.52 Hydrokote 112

Surprisingly, all eight of the prototypes tested are stable at both 25°C. and 40° C. after two and four weeks under storage conditions (seeTables 3 and 4, respectively). A 90% recovery cut-off was used as anindicator of desirable stability. Failure to meet this 90% threshold bytwo of the formulations is most likely due to manual error in thesampling process, as each of the eight formulations is expected to havesufficient stability.

TABLE 3 Stability data at Week 2 for Eight Prototype HydrocortisoneFormulations. Storage % % Impurity Prototype composition conditionRecovery RRT 0.61 RRT 1.08 RRT 1.14 RRT 1.19 Wecobee M + ColloidalSilicon 25° C./60% RH 88.3 0.16 0.02 0.03 0.05 dioxide + Hydrocortisoneacetate 40° C./75% RH 99.3 0.17 0.03 0.04 0.06 Suppocire A + ColloidalSilicon 25° C./60% RH 99.9 0.17 0.03 0.04 0.05 dioxide + Hydrocortisoneacetate 40° C./75% RH 101.8 0.17 0.03 0.04 0.05 Suppocire AS2 +Colloidal Silicon 25° C./60% RH 99.6 0.17 NA NA 0.05 dioxide +Hydrocortisone acetate 40° C./75% RH 99.5 0.17 NA NA 0.05 SuppocireBS2 + Colloidal Silicon 25° C./60% RH 100.6 0.17 0.03 0.04 0.05dioxide + Hydrocortisone acetate 40° C./75% RH 100.7 0.17 0.03 0.04 0.05Suppocire AML + Colloidal 25° C./60% RH 98.7 0.16 0.03 0.04 0.05Silicondioxide + Hydrocortisone 40° C./75% RH 101.6 0.16 0.03 0.04 0.05acetate Witepsol H 15 + Colloidal 25° C./60% RH 100.4 0.17 0.03 0.040.05 Silicondioxide + Hydrocortisone 40° C./75% RH 100.8 0.17 0.03 0.040.04 acetate Hydrokote 112 + Colloidal 25° C./60% RH 100.5 0.17 0.020.04 0.05 Silicondioxide + Hydrocortisone 40° C./75% RH 100.3 0.16 0.030.04 0.05 acetate Hydrokote 112 + Colloidal 25° C./60% RH 100.1 0.170.03 0.04 0.05 Silicondioxide + Butylated 40° C./75% RH 101.1 0.17 0.030.04 0.05 hydroxy Toulene + Hydrocortisone acetate

TABLE 4 Stability data at Week 4 for Eight Prototype HydrocortisoneFormulations. % Impurity Storage % RRT RRT RRT RRT RRT RRT RRT RRT TotalPrototype composition condition Recovery 0.422 0.631 0.797 0.920 1.1751.358 1.484 1.579 impurities Suppocire A + Colloidal Silicon 25° C./60%RH 99.2 0.15 ND <LOQ ND <LOQ <LOQ 5.05 <LOQ 0.21 dioxide +Hydrocortisone acetate 40° C./75% RH 101.9 0.18 ND <LOQ ND <LOQ <LOQ<LOQ <LOQ 0.18 Suppocire AML + Colloidal 25° C./60% RH 99.6 0.16 ND <LOQND <LOQ <LOQ 0.05 <LOQ 0.21 Silicondioxide + Hydrocortisone 40° C./75%RH 102.1 0.17 ND <LOQ ND <LOQ <LOQ 0.05 <LOQ 0.22 acetate SuppocireAS2 + Colloidal Silicon- 25° C./60% RH 85.0 0.14 ND <LOQ ND <LOQ <LOQ<LOQ <LOQ 0.14 dioxide + Hydrocortisone acetate 40° C./75% RH 100.3 0.18ND <LOQ ND <LOQ <LOQ <LOQ <LOQ 0.18 Suppocire BS2 + Colloidal Silicon-25° C./60% RH 99.3 0.16 ND <LOQ ND <LOQ <LOQ <LOQ <LOQ 0.16 dioxide +Hydrocortisone acetate 40° C./75% RH 101.1 0.17 ND <LOQ ND <LOQ <LOQ<LOQ <LOQ 0.17 Wecobee M + Colloidal Silicon- 25° C./60% RH 96.6 0.17 ND<LOQ ND <LOQ <LOQ 0.05 <LOQ 0.22 dioxide + Hydrocortisone acetate 40°C./75% RH 92.9 0.18 ND <LOQ ND <LOQ <LOQ 0.05 <LOQ 0.23 Witepsol H 15 +Colloidal 25° C./60% RH 99.6 0.16 ND <LOQ ND <LOQ <LOQ 0.05 <LOQ 0.21Silicondioxide + Hydrocortisone 40° C./75% RH 102.4 0.19 ND <LOQ ND <LOQ<LOQ 0.05 <LOQ 0.23 acetate Hydrokote 112 + Colloidal 25° C./60% RH 99.70.16 ND <LOQ ND <LOQ <LOQ 0.05 <LOQ 0.21 Silicondioxide + Hydrocortisone40° C./75% RH 99.7 0.17 ND <LOQ ND <LOQ <LOQ 0.05 <LOQ 0.22 acetateHydrokote 112 + Colloidal 25° C./60% RH 99.2 0.16 ND <LOQ ND <LOQ <LOQ0.05 <LOQ 0.21 Silicondioxide + BHT + 40° C./75% RH 99.6 0.16 ND <LOQ ND<LOQ <LOQ 0.05 <LOQ 0.21 Hydrocortisone acetate

The release of hydrocortisone acetate from each of the eightformulations was evaluated using a dissolution assay (see Example 3).For the dissolution assay, a media that contains glacial acetic acid andsodium lauryl sulfate (SLS), and which replicates the pH and environmentof the rectum, was chosen.

The dissolution profile for each of the eight formulations after fourweeks under storage conditions is shown in FIG. 1. SUPPOCIRE® A andSUPPOCIRE® AML, shows the greatest percent released over a period of 300minutes. In fact, SSUPPOCIRE® A and SUPPOCIRE® AML shows the greatestpercent released up to the 100 minute mark. Based on the dissolutionprofile shown in FIG. 1, SUPPOCIRE® A and SUPPOCIRE® AML suggests idealcandidates for formulation.

Example 3: Exemplary Dissolution Assay for Hydrocortisone Formulations

The dissolution rates of hydrocortisone acetate in the formulationsdiscussed in Example 2 and shown in FIG. 1 were determined byhigh-performance liquid chromatography (HPLC). Specifically, the sampleswere run on a reverse phase HPLC system with UV detection at 247nanometer (nm).

A protocol for the assay is described below.

Materials and Equipment Reagents and Materials

-   -   Water, HPLC grade or equivalent    -   Acetonitrile, HPLC grade or equivalent (ACN)    -   a) Reference Materials    -   Hydrocortisone USP reference standard or suitable equivalent        characterized standard.    -   b) Equipment    -   HPLC system including:        -   pump system capable of running a gradient        -   autosampler capable of injecting 10 microliter (μL)        -   UV absorbance detector capable of detection at 247 nm        -   associated computer data acquisition system    -   HPLC column: Agilent Eclipse Plus C18, 4.6×150 mm, 3.5 μm    -   Microbalance capable of weighing a minimum of 25 mg    -   Class A glassware

Safety Requirements

-   -   General personal protection attire (lab coat, gloves, safety        goggles, etc.) should be worn at all times.

Preparation of Solutions

-   -   Alternate volumes of any preparation may be prepared by        adjusting volumes and weights proportionately, with the        exception that the weight of the standard preparations may not        be reduced.

Preparation of Mobile Phase A

-   -   Water is used as mobile phase A. Obtain 1 L of Water. Degas

Preparation of Mobile Phase B

-   -   ACN is used as mobile phase B. Obtain 1 L of Acetonitrile. Degas

Preparation of Standard Solution

-   -   If a stable standard is available for which standard agreement        has already been demonstrated, preparation of fresh standards        may be omitted. Accurately weigh and transfer approximately 25        mg±2.5 mg of Hydrocortisone reference standard material to a 250        milliliter (mL) volumetric flask. Dissolve in and dilute to        volume with Acetonitrile and mix well. Prepare in duplicate (S1        and S2). Nominal concentration: 0.1 mg/mL of Hydrocortisone.

Dissolution Testing Procedure

-   -   Weigh each suppository unit.    -   Set up the dissolution bath to USP Apparatus I (Baskets).    -   Equilibrate 900 mL of appropriate medium to 37° C. in each        vessel used.    -   Place one suppository unit in each basket and begin rotation at        50 RPM.    -   Withdraw 5 mL from each vessel at 15, 30, 45, and 60 minutes        (min).    -   After 60 minutes, increase the paddle speed to 150 RPM and        withdraw 5 mL at 90 minutes.    -   Filter each sample through a 0.45 μm Nylon syringe filter        discard the first 3 mL of the filtrate and use the rest for HPLC        analysis.

Chromatographic Procedure

-   -   HPLC Conditions    -   Mobile Phase A: Water    -   Mobile Phase B: Acetonitrile (ACN)    -   Column: Agilent Eclipse Plus C18, 4.6×150 mm, 3.5μm    -   Guard column: Frit    -   Column Temperature: 30° C.    -   Injection Volume: 10 μL    -   Detection Wavelength: 247 nm    -   Run Time: 45 minutes    -   Flow Rate: 1.0 mL/minute    -   Isocratic Flow: 50% A: 50% B    -   Autosampler temperature: Ambient    -   Hydrocortisone Acetate (Approx. RT): 3.6 minutes

Test Procedure

-   -   Perform any number of equilibration injections of any standard        prior to starting the analysis sequence. Do not re-inject from        the vial used for equilibration injections after equilibration        is complete. Clearly identify the equilibration injections as        data not used. During analysis, it is preferable but not        required to perform no more than one injection from a single        vial.    -   Determine system suitability at the beginning of the sequence        with five injections of S1, two injections of S2 and at least        one Diluent injection. System suitability injections may be        performed in any order.    -   Sample injections should be bracketed by standard injections and        no more than twelve samples should be run within a bracket. A        standard that passes the criterion mentioned in Precision        section, relative to one other standard preparation must be used        as a bracketing standard.

System Suitability

-   -   Precision    -   Calculate the average peak area and % RSD obtained for the        Hydrocortisone peak in each of the initial five standards (S1)        injections. The % RSD must be ≤2.0.    -   For each bracketing standard throughout the run, calculate the %        difference for the Hydrocortisone peak area in comparison to the        average Hydrocortisone peak area from the five precision        injections. The % difference for each bracketing standard must        be ≤3.0.

Standard Agreement

-   -   Compare the average peak area for Hydrocortisone in the five        system suitability injections of standard S1 with the peak area        for Hydrocortisone in the two injections of standard S2.        Agreement must be within 100.0±2.0%.    -   Standard agreement may be omitted from system suitability        evaluation if a standard within its stability window has been        shown to agree with another standard for Hydrocortisone.

Non-Interference

-   -   No significant interference greater than 0.05% of the        Hydrocortisone average standard area (n=5) should be seen in an        injection of Diluent.

Tailing Factor

-   -   The tailing factor for Hydrocortisone peak calculated for all        the system suitability injections and bracketing standards must        be ≤2.0.

Calculations and Reporting Integration of Peaks

-   -   Set the minimum peak area for integration to not more than 0.05%        of the average Hydrocortisone injector precision peak area. For        all system suitability standard injections, integrate        Hydrocortisone peak. Accurately integrate all the peaks in a        sample chromatogram. It is permissible not to integrate peaks        resulting from Diluent.    -   Standard Solution Concentration        -   Calculate the concentration of Hydrocortisone in the            standard as follows:

${{Concentration}\mspace{14mu} \left( {{mg}/{mL}} \right)} = \frac{W\; 1 \times {PF}}{25\mspace{14mu} {mL}}$

-   -   -   Where:            -   W1=weight of standard used to prepared the standard (mg)            -   PF*=purity factor of the reference standard taken from                the certificate of analysis (in decimal form)                -   Calculation of Drug Substance Content

    -   Calculate the % of Hydrocortisone in samples as follows:

$\% = {\frac{\left( {\left( \frac{{Area}_{smpl}}{{Area}_{std}} \right) \times {SC}} \right)}{\left( \frac{W\; 1}{{V\; 1} - {N \times 5}} \right)} \times 100}$

-   -   Where:        -   Area_(Smpl)=Area of Urea in the sample        -   Area_(Std)=Area of Urea in the five precision standard            injections        -   SC=Standard concentration (mg/mL)        -   W1=Nominal weight of the Hydrocortisone in a unit, typically            90 mg            -   V1=Vessel volume (typically 900 mL)

N Time point (minutes) 0 15 1 30 2 45 3 60 4 90

Example 4: Development and Characterization of Hydrocortisone AcetateFormulations Containing Colloidal Silicon Dioxide

The studies herein include formulating different prototypes ofhydrocortisone acetate suppositories and evaluating the prototypes forphysical and chemical stability prior to refining the formulations basedupon critical quality attributes (CQAs), such as melting point and theActive Pharmaceutical Ingredient (API) release profile. The final drugproduct that was chosen is a solid body of 2 g weight containing 90 mgof API in a fatty base adapted for introduction into the rectal orificeof the human body, which melts at about body temperature.

The studies herein have also evaluated aluminum shells and plasticshells for container closure system and found that both aluminum andplastic shells are compatible with the product based upon parameterssuch as ease of filling, visualization of the filled product, andproduct sticking to the shells. The current container closure system forthe products are plastic suppository shells which accommodate up to 2grams of product.

The selection of base is one of the important aspects in the developmentof the suppositories. The selected base can influence the mechanism ofaction. Initially, placebo prototypes 1-10 (compositions shown in Table5) were made to evaluate the aesthetics and ease of filling. The baseswere weighed according to the composition and melted. The colloidalsilicon dioxide was then added to the melted base and solubilized (forprototypes with colloidal silicon dioxide). The melted preparation wasthen poured into the shells. During the filling operation, it wasobserved that prototypes 1, 2, and 3 were very viscous and difficult tofill into the shells even at higher temperatures such as 80 degreesCelsius (° C.). Conversely, prototypes 4-10 were less viscous whencompared to prototypes 1, 2, and 3 and were easy to fill into the shellsat a temperature of 50° C. The shells were sealed and the suppositorieswere allowed to solidify. After a few days, the suppositories wereevaluated for aesthetics. Prototypes 1, 2, and 3 exhibited cracks in thesuppositories whereas prototypes 4-10 did not exhibit any cracks.

TABLE 5 Compositions of Various Placebo Prototypes (% w/w). PrototypeMaterial 1 2 3 4 5 6 7 8 9 10 PEG 300 60 10 PEG 8000 40 PEG 1450 30 65PEG 3350 70 25 Suppocire 99.3 AML Suppocire 99.3 A Suppocire 99.3 AS2Suppocire 99.3 BS2 Witepsol 99.3 H-15 Wecobee 99.3 M Hydrokote 99.3 112Colloidal 0.7 0.7 0.7 0.7 0.7 0.7 0.7 silicon dioxide

The Table 5 observations and previous published studies indicate thatPEG-based suppositories can cause irritancy. Thus, prototypes 1, 2, and3 were eliminated from further study. Building upon the data that wasprovided in Table 5, active formulations using hydrocortisone acetate(90 mg) were prepared. The compositions of active prototypes 11-17 areshown in Table 6. The active prototypes were kept in stability chambersat two conditions: 1) 25° C./60% relative humidity (RH); and 2) 40°C./75% RH, for one month prior to the stability study that were used toevaluate physical and chemical stability.

TABLE 6 Compositions of Active Prototypes Prototype 11 12 13 14 15 16 17% % % % % % % Material w/w w/w w/w w/w w/w w/w w/w Suppocire AML 94.8Suppocire A 94.8 Suppocire AS2 94.8 Suppocire BS2 94.8 Witepsol H-1594.8 Wecobee M 94.8 Hydrokote 112 94.8 Colloidal 0.7 0.7 0.7 0.7 0.7 0.70.7 silicon dioxide Hydrocortisone 4.5 4.5 4.5 4.5 4.5 4.5 4.5 acetate

The suppositories in Table 6 were evaluated for physical stability suchas cracks within the suppositories, discoloration and feel. Prototypes11-17 did not exhibit cracks within the suppositories, discoloration orunsatisfactory feel. The suppositories in Table 6 were then stored at40° C./75% RH and allowed to solidify at room temperature for furtherevaluations.

Prototypes 11-17 were next evaluated for Critical Quality Attributes(CQAs) such as melting point (as the mechanism of action for fat basedsuppositories is melting), and release profile for the API in order toidentify the lead formulation. Table 7 shows the melting point data forprototypes 11-17.

TABLE 7 Melting Point Data for the Active Prototypes. Melting MeltingMelting Melting Melting temperature temperature temperature temperaturetemperature Prototype (° C.) Trial 1 (° C.) Trial 2 (° C.) Trial 3 (°C.) Trial 4 (° C.) Trial 5 Average 11 38.25 38.00 38.25 37.00 37.5037.80 12 37.75 37.50 38.50 39.50 38.00 38.25 13 39.00 38.25 38.50 40.5039.00 39.05 14 39.50 38.50 39.00 37.50 39.00 38.70 15 37.25 36.00 38.0036.00 39.00 37.25 16 37.50 39.00 39.00 38.50 40.50 38.90 17 43.00 43.5042.00 43.50 42.00 42.80

Table 7 shows that the average melting point of prototypes 11-16 isbetween approximately 37° C. to 39° C. The average melting point ofprototype 17 was found to be slightly higher at approximately 43° C. Asthe melting point of all the prototypes studied was found to be quiteclose, the API release profile was next evaluated to identify the leadformulation from the group of prototypes.

Example 5: Development of a Dissolution Method for Testing SuppositoryFormulations

In order to assess the API release profile from the prototypes inExample 4 to identify a lead formulation, a robust dissolution methodwas developed. Solubility studies were performed on the API for theselection of dissolution media. For these studies, the activeconcentration of the dissolution media was 0.1 milligrams per milliliter(mg/mL). The results of the solubility of 0.1 mg/mL hydrocortisoneacetate in various dissolution medias is shown in Table 8.

TABLE 8 Solubility of API (0.1 mg/mL) in Various Dissolution Media. %Solubility Dissolution media API 0.5% Tween 30  12.4  3% Tween 80 20.6Phosphate buffer pH 7.2 4.1 0.5% w/v SLS  57.6 3% w/v SLS 73.5 5% w/vSLS 99.7 10% w/v SLS  98.7 SLS = sodium lauryl sulfate

According to USP guidelines (on sink conditions) the solubility needs tobe at least 3 times the proposed active concentration. As shown in Table8, sodium lauryl sulfate (SLS) achieved the highest percent solubilityof the API (hydrocortisone acetate). The studies next turned to the useof higher hydrocortisone acetate concentrations (0.3 mg/mL). Thesolubility of 0.3 mg/mL hydrocortisone acetate in various dissolutionmedia is shown in Table 9.

TABLE 9 Solubility of hydrocortisone acetate (0.3 mg/mL) in SLSDissolution Media. Dissolution media % Solubility  5% w/v SLS 98.9 10%w/v SLS 99.3

As shown in Table 9, the solubility percent of 0.3 mg/mL hydrocortisoneacetate in SLS still remained high. In order to avoid ionization of thehydrocortisone acetate in the dissolution media, a buffer of pH 5.0 wasused in combination with 5% w/v SLS. The final composition of thedissolution media was 5% w/v SLS:acetate buffer (pH 5.0) in 70:30combination with the pH of the final combination adjusted to 6.8-7.0.The average recovered solubility of 0.3 mg/mL hydrocortisone acetate inthe proposed dissolution media was 98.4%.

According to the results shown in Tables 8 and 9, the optimizeddissolution parameters include:

-   -   Dissolution media: 5% w/v SLS: acetate buffer pH 5.0 (70:30)        final pH adjusted to 6.8-7.0.    -   USP Apparatus II (Paddles).    -   Dissolution volume: 900 mL.    -   Rotations per minute (RPM): 50.    -   Temperature: 37° C.    -   Time points: 15 min, 30 min, 60 min, 90 min, 120 min, 180 min,        and 360 min.

Prototypes 11-17 were then tested for hydrocortisone acetate releaseunder the optimized dissolution parameters obtained from Table 9. Table10 shows the hydrocortisone acetate release profile of prototypes 11-17.

TABLE 10 Percent Hydrocortisone Acetate Released with Respect to Timefor the Prototypes. % API released after respective time (min) Prototype15 30 60 90 120 180 360 11  9.66 22.13 42.09 58.92 72.73 89.39 98.82 12 6.76  9.55 15.29 21.20 27.00 35.70 52.31 13  7.23 14.96 31.93 46.1757.96 73.89 89.76 14  1.32  4.25 11.05 15.68 18.99 23.72 30.22 15 13.2524.27 37.93 49.35 62.32 77.53 90.42 16  1.35  3.00  4.89  6.33  7.52 9.35 13.39 17  6.39 16.02 42.09 68.88 86.12 93.51 94.10

As shown in Table 10, prototypes 11, 13, 15, and 17 were identified ashaving the best dissolution. The dissolution profile for each of theprototypes 11-17 is shown in FIG. 2. Prototypes 11, 13, 15, and 17 showthe greatest percent of hydrocortisone acetate released over a period of350 minutes. In fact, prototypes 11, 13, 15, and 17 show the greatestpercent of hydrocortisone acetate released at 150 minutes. Based on thehydrocortisone acetate release profile for each of the prototypes shownin FIG. 2, prototypes 11, 13, 15, and 17 were selected for leadformulation.

Based on the melting point profile (Table 7), release profile (Table 10)and FIG. 2, prototypes 11, 13, 15, and 17 were identified as the leadformulations. However, prototypes 13 and 17 were removed from thestudies by taking into consideration the compendial status of the baseused in prototype 17 and the high melting point of prototype 13. Thus,prototypes 11 and 15 were selected as the top two formulations (Table11).

TABLE 11 Composition of the Lead and Backup Formulations. CompositionPrototype Ingredient (% w/w) 11 Suppocire AML 94.8 Colloidal silicondioxide 0.7 Hydrocortisone acetate 4.5 15 Witepsol H-15 94.8 Colloidalsilicon dioxide 0.7 Hydrocortisone acetate 4.5

Taking the composition of WITEPSOL® H-15 base (contains hydrogenatedcoco-glycerides which might have polymorphism issues) intoconsideration, prototype 15 was selected as the backup formulation.Thus, the prototype 11 composition containing SUPPOCIRE® AML, base(Table 12) was selected as the lead formulation.

TABLE 12 Composition of the Lead Formulation. Composition per 2 gramMaximum IIG Ingredient No. Ingredient Grade Function suppository limit 1Hydrocortisone acetate USP API 90 mg NA 2 Suppocire AML USP/NF/JP Base1896 mg  1920 mg 3 Colloidal silicon dioxide NF Suspending agent 14 mg 14 mg IIG = United States Food & Drug Administration's “InactiveIngredient Guide” USP = United States Pharmacopeia NF = JPE = NA = notapplicable

The results from these studies led to the selection of the SUPPOCIRE®AML active prototype formulation as the lead formulation based on itssuperior physical and dissolution properties. The selected leadformulation includes hydrocortisone acetate 90 mg, colloidal silicondioxide 14 mg and SUPPOCIRE® AML 1896 mg, which provides a suppositorywith a total weight of 2 g. This lead formulation was then subjected tophysical and chemical stability, and dissolution studies.

Physical and Chemical Stability Studies of the Lead Formulation

The selected lead formulation (prototype 11: hydrocortisone acetate 90mg, colloidal silicon dioxide 14 mg and SUPPOCIRE® AML 1896 mg) wassubjected to physical and chemical stability studies. The study employedtwo storage conditions in order to demonstrate compatibility with theselected excipients and to give confidence that the formulations areappropriate for longer storage. The conditions include:

-   -   25±2° C. I 60±5% RH (relative humidity)=standard storage        conditions    -   40±2° C. I 75±5% RH (relative humidity)=accelerated storage        conditions

The results of the physical and chemical stability studies showing theassay and impurity results for SUPPOCIRE® AML active prototypes understorage conditions (standard and accelerated) are summarized in Table14.

TABLE 13 Assay and Impurities Results for SUPPOCIRE ® AML-ContainingPrototype (Hydrocortisone Acetate 90 mg and Colloidal Silicon Dioxide 14mg). T = 0 T = 1 month T = 1 month T = 2 month T = 2 month T = 3 month T= 3 month sample @ 25/60 @ 40/75 @ 25/60 @ 40/75 @ 25/60 @ 40/75 PeakName % L.C. % L.C. % L.C. % L.C. % L.C. % L.C. % L.C. Hydrocortisone98.6 97.5 98.4 96.9 101.3 97.3 99.8 acetate RRT 0.601 ND ND ND ND ND<LOQ <LOQ RRT 0.623 0.18 0.16 0.17 0.16 0.19 0.15 0.16 RRT 0.823 ND NDND ND ND 0.08 <LOQ RRT 0.860 <LOQ <LOQ 0.05 <LOQ 0.06 <LOQ <LOQ RRT0.889 ND ND ND ND ND <LOQ <LOQ RRT 0.937 <LOQ <LOQ <LOQ <LOQ <LOQ <LOQ<LOQ RRT 0.968 ND ND ND ND ND <LOQ <LOQ RRT 1.075 <LOQ <LOQ <LOQ <LOQ<LOQ <LOQ <LOQ RRT 1.145 <LOQ <LOQ 0.05 0.05 <LOQ <LOQ <LOQ RRT 1.1860.05 0.05 <LOQ 0.06 0.05 <LOQ <LOQ RRT 1.332 <LOQ <LOQ <LOQ <LOQ <LOQ<LOQ <LOQ Total 0.23 0.21 0.27 0.27 0.30 0.23 0.16 Impurities % L.C. = %Label Claim RRT = Relative Retention Time ND = not detected <LOQ = Lessthan Limit Of Detection

The results from the initial and one month through three month stabilitystudies for the lead prototype (SUPPOCIRE® AML with hydrocortisoneacetate 90 mg and colloidal silicon dioxide 14 mg) shows negligibleamounts of total impurities after three months of storage (Table 13).These studies demonstrate that the lead formulation remains stable forat least three months under the conditions tested.

Dissolution Studies

The selected lead formulation 11 (hydrocortisone acetate 90 mg,colloidal silicon dioxide 14 mg and SUPPOCIRE® AML 1896 mg) was nextsubjected to dissolution studies (Table 14). Samples stored at both 25°C./60% RH and 40° C./75% RH were subjected to the dissolution testing.Samples stored at 25° C./60% RH were subjected to dissolution testing atinitial (Time (T)=0), 1 month (T=1) and 2 months (T=2) of storage.Samples stored at both 25° C./60% RH and 40° C./75% RH were subjected totesting at 3 months (T=3) and 7 months (T=7) of storage.

TABLE 14 Dissolution Profiles for SUPPOCIRE ® AML Formulation withHydrocortisone Acetate 90 mg and Colloidal Silicon Dioxide 14 mg (T = 0to T = 7). Active with Suppocire AML (Average of n = 6 vessels) 3 month3 month 7 month 7 month Time 25° C./60% 40° C./75% 25° C./60% 40° C./75%(Min) Initial 1 month 2 month RH RH RH RH 15 11.09 6.97 8.46 8.58 7.526.87 7.48 30 21.83 18.56 22.94 20.50 14.09 19.24 12.46 60 45.49 37.6245.78 38.34 25.17 39.33 18.48 90 63.71 50.93 63.10 54.69 40.39 55.9221.93 120 78.29 62.74 76.09 66.41 46.35 69.68 25.64 180 93.22 83.1490.59 86.67 50.79 87.42 32.03 360 99.01 97.49 98.16 98.53 68.42 100.3049.05

The results of the dissolution studies (Table 14) show that thedissolution profile for hydrocortisone acetate remains consistent evenafter 7 months of storage at standard storage conditions (25° C./60%RH). However, storage at accelerated conditions (40° C./75% RH) after 7months resulted in a decrease of hydrocortisone acetate release from thelead formulation.

These results led to the selection of a SUPPOCIRE® AML active prototypeformulation with hydrocortisone acetate 90 mg and colloidal silicondioxide 14 mg as the lead formulation for the hydrocortisone acetatesuppository studies based on its desirable properties, as indicated bythe assay results (Table 13) and dissolution release profile (Table 14).

Example 6: Hydrocortisone Acetate (90 mg) Suppository Specification andDissolution Profile

The specification and dissolution profile for the 2 gram suppositorycontaining 90 mg of hydrocortisone acetate and colloidal silicon dioxide(prototype 11) is shown in Table 15.

TABLE 15 Two Gram Suppository (Hydrocortisone Acetate 90 mg)Specification and Dissolution Profile. Test Method SpecificationsInitial 30 Day Film Seal Integrity Visual Film Tightly Sealed Pass PassAppearance Visual White to off white bullet Pass Pass shaped suppositoryfree from visible contamination and cracks Melting Temperature USP <741>Report Value 35.5 C. 35.9 C. Assay DOP-QC-224 90.0%-110.0% 100.70%100.10% Related Substances DOP-QC-224 Hydrocortisone Report % 0.25%0.23% 17-dehydro-21 Report % 0.06% 0.05% hydroxy hydrocortisoneIndividual Unknown Impurities Report % <0.05% RRT 0.84, 0.03% and RRTRRT 0.93, 0.03% Total Unknown Impurities Report % <0.05% 0.05%Dissolution DOP-QP-225 15 minutes Report % 12.0% 6.7% 30 minutes Report% 21.9% 16.8% 60 minutes Report % 34.9% 30.7% 90 minutes Report % 46.6%40.0% 120 minutes Report % 59.0% 48.9% 180 minutes Report % 80.8% 64.5%360 minutes Report % 97.3% 82.4% 375 minutes Report % 98.3% 99.5% TotalAerobic Plate Count DOP-QC-114 NMT 2000 cfu/g NMT 10 N/A USP <61> TotalCombined Yeast and Mold DOP-QC-114 NMT 200 cfu/g NMT 10 N/A USP <61>

The hydrocortisone acetate (90 mg) suppository was packaged in 2 grampolyethylene/polyvinyl chloride (PE/PVC) suppository shells andsubjected to standard CQAs for 60 days under 40° C./75% RH storageconditions. As shown in Table 15, the appearance, melting temperatureand stability of the 2 g suppository hydrocortisone acetate 90 mgremained constant and virtually unchanged after 60 days of storage underaccelerated conditions (40° C./75% RH). Total impurities that weregenerated over a period of 60 days remained negligible (<0.05%) underaccelerated storage conditions (40° C./75% RH). Moreover, thedissolution studies under our standard protocol have also shown that the2 g suppository releases at least about 80% of the hydrocortisoneacetate at about 180 minutes following exposure to dissolution mediacomprising 5% w/v sodium lauryl sulfate:acetate buffer pH 5.0 (70:30)final pH adjusted to 6.8-7.0. At about 360 minutes following exposure todissolution media comprising 5% w/v sodium lauryl sulfate:acetate bufferpH 5.0 (70:30) final pH adjusted to 6.8-7.0, the 2 g suppositoryreleases at least about 97% of the hydrocortisone acetate.

Specifications and Analytical Procedures for Examples 4 to 6

The CQAs are melting point, release profile, color, appearance, contentuniformity, assay and dissolution study. The specifications for the CQAsare shown in Table 16.

TABLE 16 Specifications for the CQAs. Test Limits Method A. AppearanceWhite to off-white no cracks within suppositories Visual B.Hydrocortisone Acetate HPLC RT value in sample corresponds toM-CCO-LC-002 Identification* hydrocortisone acetate reference standardC. Assay 98.0-102.0% of label claim M-CCO-LC-002 D. Within Batch ProcessAssay range: M-CCO-LC-002 Homogeneity (beginning, 90.0%-110.0% middle,and end samples)* RSD NMT 6% E. Dissollution Report Results M-CCO-LC-001F. Degradation Products: Report Results M-CCO-LC-002 Individual UnknownImpurities Total Impurities G. Melting Point Report Results USP <741> H.Content Uniformity* The acceptance criteria per USP<905> is M-CCO-LC-002AV (Acceptance Value) is NMT 15.0% (n = 10). If n = 10 fails to meet thecriteria, then Content Uniformity (CU) will be performed on additional20 units (stage- 2) and the AV value is calculated for a total of 30units. The acceptance criteria is AV NMT 15.0% (n = 30). *= Tests willbe performed only on initial T-zero samples. NMT = No More Than

Analytical Procedures

General experimental techniques for Examples 4-6 can be accomplished bythe methods described herein.

General Dissolution Method: M-CCO-LC-001 and DOP-QC-225

HPLC Column: Agilent Eclipse Plus C18, 4.6×150 mm, 3.5 μm.

Preparation of Dissolution Media: Prepared 5% w/v sodium lauryl sulfate:acetate Buffer pH 5.0 (70:30), and adjusted the final pH to 6.8.Preparation of Standard Solution: Prepared a standard solutioncontaining about 0.1 mg/mL hydrocortisone reference standard indissolution medium.Preparation of Samples: Hydrocortisone Acetate Suppository samples weresubjected to dissolution experiment and sampled at specified time pointsas described in the test method.

General Assay Method: M-CCO-LC-002 and DOP-QC-224

HPLC Column: Agilent Eclipse Plus C18, 4.6×150 mm, 3.5 μm.

Preparation of Standard Solution: Prepared a standard solutioncontaining about 0.18 mg/mL hydrocortisone acetate reference standard inacetonitrile.

Preparation of Samples: Prepared sample solutions containing about 0.18mg/mL hydrocortisone acetate sample in acetonitrile.

Dissolution Method

Reagents and Materials

Water, HPLC grade or equivalentAcetonitrile, HPLC grade or equivalent (ACN)Sodium Acetate Trihydrate, ACS gradeSodium Lauryl Sulfate (SLS), NF grade2 Normal (N) Acetic acid5N Sodium hydroxide (NaOH), ACS grade

Reference Materials

Hydrocortisone Acetate, United States Pharmacopeia (USP) referencestandard or suitable equivalent characterized standard.

Equipment

HPLC system including:

-   -   Pump system capable of running a gradient    -   Auto sampler capable of injecting 10 μL    -   UV absorbance detector capable of detection at 247 nm    -   Associated computer data acquisition system        HPLC column: Agilent Eclipse Plus C18, 4.6×150 mm, 3.5 μm        Microbalance capable of weighing a minimum of 25 mg        Class A glassware        0.45 μm Polytetrafluoroethylene (PTFE) syringe filter

Spring Style Capsule Sinker, 316 SS, QLA, Part # CAPWST-31

Preparation of Mobile Phase A

Water is used as mobile phase A. Obtain 1 L of Water. Degas.

Preparation of Mobile Phase B

ACN is used as mobile phase B. Obtain 1 L of Acetonitrile. Degas.Note: Premixed solution of (50:50) ACN:Water can also be used as mobilephase.

Preparation of Standard Solution

If a stable standard is available for which standard agreement hasalready been demonstrated, preparation of fresh standards may beomitted. Accurately weigh and transfer approximately 25±2.5 mg ofHydrocortisone Acetate reference standard material to a 250 mLvolumetric flask. Add 250 ml of ACN. Heat it in oven at 70° C. for 30minutes and sonicate to dissolve. Cool it to room temperature. Dilute tovolume with dissolution media and mix well. Nominal concentration: 0.1mg/mL of Hydrocortisone Acetate.

Preparation of 5% weight/volume (w/v) Sodium Lauryl Sulfate

Dissolve 50 g of Sodium Lauryl Sulfate in 1 L of water. Heat thesolution if necessary to ensure dissolution. Scale as necessary.

Preparation of Acetate Buffer pH 5.0

Dissolve 20 g of Sodium Acetate trihydrate in 4 L of water. Add 26 mL of2N acetic acid. Adjust the pH to 5±0.05 with 2N acetic acid. Scale asnecessary.

Dissolution Media

For each liter of dissolution media, combine 700 mL of 5% w/v SLS and300 mL of Acetate buffer pH 5.0. Adjust the pH to 6.8±0.05 with 5N NaOH.Sonicate for 30 min.

Dissolution Testing Procedure

-   -   Weigh each suppository unit.    -   Set up the dissolution bath to USP Apparatus 2 (Paddles).    -   Equilibrate 900 mL of dissolution media to 37° C. in each vessel        used.    -   Place one suppository unit in each sinker, drop it in the vessel        and begin rotation at 50 rotations per minute (RPM).    -   Withdraw 5 mL from each vessel at 15, 30, 60, 90, 120, 180 and        360 minutes.    -   After 360 minutes, increase the speed to 150 RPM and withdraw 5        mL after 15 min.    -   Filter each sample through a 0.45 μL PTFE syringe filter discard        the first 3 mL of the filtrate and use the rest for HPLC        analysis.        Note: Samples are stable for 4 days at room temperature.

Chromatographic Procedure

Mobile Phase A: Water Mobile Phase B: Acetonitrile Column: AgilentEclipse Plus C18, 4.6×150 mm, 3.5 μm

Guard column: Frit

Column Temperature: 30±3° C. Injection Volume: 10 μm DetectionWavelength: 247 nm

Run Time: 10 minutesFlow Rate: 1.0±0.1 mL/minute

Isocratic Flow: 50% A: 50% B(±10%)

Auto sampler temperature: AmbientRetention Time: Approximately 3.6 minutes for Hydrocortisone Acetate

Assay Method

Reagents and Materials

Water, HPLC grade or equivalentAcetonitrile, HPLC grade or equivalent (ACN)Triflouroacetic Acid, HPLC grade or equivalent (TFA)

Reference Materials

Hydrocortisone Acetate USP reference standard or suitable equivalentcharacterized standard.

Equipment

HPLC system including:

-   -   Pump system capable of running a gradient    -   Auto sampler capable of injecting 10 μL    -   UV absorbance detector capable of detection at 247 nm    -   Associated computer data acquisition system    -   column heater capable of heating to 30° C.        HPLC column: Agilent Eclipse Plus C18, 4.6×150 mm, 3.5 μm        Microbalance capable of weighing a minimum of 36 mg        Class A glassware        0.20 μm PTFE syringe filter

Preparation of Mobile Phase A (0.1% TFA in Water)

Obtain 1 L of Water. Add 1 mL of TFA. Mix well and degas.

Preparation of Mobile Phase B (0.1% TFA in ACN)

Obtain 1 L of ACN. Add 1 mL of TFA. Mix well and degas.

Preparation of Standard Solution

If a stable standard is available for which standard agreement hasalready been demonstrated, preparation of fresh standards may beomitted. Accurately weigh and transfer approximately 36±3 mg ofHydrocortisone Acetate reference standard material to a 200 mLvolumetric flask. Add 150 ml of ACN. Sonicate if necessary. Dilute tovolume with ACN and mix well.Nominal concentration: 0.18 mg/mL of Hydrocortisone Acetate.Stability of Standard: Standard solution is stable for 11 days at roomtemperature.

Preparation of Samples for Assay

Accurately weigh 5 units of suppositories and transfer into a 1000 mLvolumetric flask and add 500 mL of Acetonitrile using an appropriategraduated cylinder. Place a stir bar and heat it in a water bath at 70°C. for 30 minutes at 700 RPM. Remove the stir bar and cool to roomtemperature. Mix well. Filter 10 mL of sample through a 0.20 μm PTFEsyringe filter to a 10 mL plastic syringe. Discard the first 3 mL andcollect the filtrate to a scintillation vial. Pipette 5.0 mL of thefiltrate to a 25 mL volumetric flask and dilute to volume with ACN. Mixwell.Nominal concentration: 0.18 mg/mL of Hydrocortisone Acetate.Stability of Sample: Sample solution is stable for 6 days at roomtemperature.

Preparation of Samples for Content Uniformity

Accurately weigh out a unit of suppository and transfer into a 500 mLvolumetric flask and approximately add 400 mL of Acetonitrile. Place astir bar in the flask and heat it in a water bath at 70° C. for 30minutes at 700 RPM. Remove the stir bar and cool to room temperature.Dilute to volume with Acetonitrile and mix well. Filter 5 mL of samplethrough a 0.20 μm PTFE syringe filter to a 5 mL plastic syringe. Discardthe first 3 mL before collecting sample for analysis. Nominalconcentration: 0.18 mg/mL of Hydrocortisone Acetate.Stability of Sample: Sample Solutions is stable for 6 days at roomtemperature.

HPLC Conditions

Mobile Phase A: 0.1% TFA in Water Mobile Phase B: 0.1% TFA in ACNColumn: Agilent Eclipse Plus C18, 4.6×150 mm, 3.5 μm

Guard column: Aquasil C18 or equivalent

Column Temperature: 30° C. Injection Volume: 10 μm Detection Wavelength:247 nm

Run Time: 35 minutesFlow Rate: 1.0 mL/minuteAuto sampler temperature: AmbientGradient program:

Time (Minutes) % A % B 0 75 25 20 25 75 23 25 75 25.1 75 25 35 75 25Retention Time: Approximately 10.7 minutes for Hydrocortisone Acetate

USP <741>: U.S. Pharmacopeia Monograph 741—Melting Range or Temperature

USP <905>: U.S. Pharmacopeia Monograph 905—Uniformity of Dosage Units

USP <61>: U.S. Pharmacopeia Monograph 61—Microbial Examination ofNonsterile Products

Example 7: Manufacturing Process for Hydrocortisone Acetate SuppositoryFormulation

The lead formulation was manufactured (both active and placebo) andsubjected to stability studies at two different conditions: 1) 25°C./60% RH; and 2) 40° C./75% RH.

Preparation of the Base:

The stainless steel vessel identification number and tare weight wasrecorded. Into the vessel, was add the weighed amount of base and beginmelting the base using a hot stir plate and water bath, low shearsweep/side scrape mixing (hand mix was used in the lab for small scaleoperations) until all the base was completely melted. The temperaturewas maintained at 55±5° C. (T_(f)).

Addition of Colloidal Silicon Dioxide:

A silverson mixer (or similar homogenizer) was set up. The requiredamount of colloidal silicon dioxide was weighed and added to the meltedbase. The colloidal silicon dioxide was then allowed to hydrate bymixing using a square shape mesh. The mixing speed was maintainedbetween 3000-3500 RPM. The temperature was maintained at 55±5° C.(T_(f)).

Addition of Hydrocortisone Acetate:

The required amount of hydrocortisone acetate was weighed and added tothe main batch while mixing with homogenizer set at 4000-4500 RPM andequipped with a square shape mesh for ten minutes or until visiblyuniformly dispersed. The temperature was maintained at 55±5° C. (T_(f)).

Filling Process:

Begin mixing the batch using a propeller type mixer (e.g. IKA) at500-1500 RPM. The suspended hydrocortisone acetate must be kept fromsettling during the filling operation. Maintain batch temperaturebetween 50-60° C. Set up a peristaltic pump (or similar) along with thetubing and adjust the settings so that it dispenses two grams of productin each cycle. The tubing was maintained at 50-60° C. with the help of aheat tape to avoid product congealing in the tube during filling intothe suppositories. Dispense one cycle of product into each suppositoryform and allow to cool to room temperature. The cooling process may beaccelerated by placing the filled forms into a cooling tunnel (orequivalent).

The relevant teachings of all patents, published applications andreferences cited herein are incorporated by reference in their entirety.

While this invention has been particularly shown and described withreferences to example embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the scope of the inventionencompassed by the appended claims of this provisional application or alater-filed non-provisional application claiming priority hereto.

What is claimed is:
 1. A drug delivery element comprising: a componenthaving a first shape external from a rectum and configured to form asecond shape internal to the rectum, the second shape having aconfiguration to expose a drug to tissues of the rectum.
 2. The elementof claim 1, wherein the first shape is configured for passage throughthe anus, and the second shape is configured to maintain placement inthe rectum for a duration of time.
 3. The element of claim 1, whereinthe first shape has less volume or surface area than the second shape.4. The element of claim 1, wherein the component is a solid orsemi-solid component.
 5. The element of claim 1, wherein the componentis configured to unfold or expand to form the second shape.
 6. Theelement of claim 1, wherein the component includes a ring
 7. The elementof claim 6, wherein the ring is folded into a loop within a loop whenthe component has the first shape.
 8. The element of claim 1, whereinthe component includes a central portion and plural arms extending fromthe central portion.
 9. The element of claim 8, wherein the centralportion and arms are arranged in a tree configuration.
 10. The elementof claim 8, wherein the central portion and arms are arranged to allowgas flow through the central portion.
 11. The element of claim 8,wherein the arms are substantially straight.
 12. The element of claim 8,wherein the arms are in the shape of petals.
 13. The element of claim 1,wherein the component comprises a medicated film or fabric.
 14. Theelement of claim 1, wherein the component includes one or more filamentsconfigured to expose the drug to the tissue.
 15. A drug delivery elementcomprising: a shell defining an internal cavity configured to contain anactive drug ingredient in a stable form and wherein the shell is furtherconfigured to release the active drug ingredient following placementinto a rectum.
 16. The element of claim 15, wherein the shell isconfigured to dissolve following placement into the rectum.
 17. Theelement of claim 15, wherein the hydrocortisone acetate or the activedrug ingredient is released in a new form.
 18. The element of claim 17,wherein the new form is different from the stable form.